Résumé
Metastasis is responsible for most breast cancer mortalities and 30% of the patients with breast cancer will develop metastases. Despite the establishment of efficient targeted therapies for breast cancer, there is no cure for metastatic disease. Our research team have developed a potent, highly selective, small molecule inhibitor of casein kinase-1 delta (CK1δ), a serine/threonine kinase. We have demonstrated that our lead molecule (SR-3029) provokes tumor specific cell death and tumor regression in pre-clinical orthotopic xenograft models of triple negative breast cancer (TNBC) including, basal-like patient derived (PDX) breast cancer models. Herein, we demonstrate that targeting CK1δ inhibits tumor cell invasion in cell based studies and markedly reduces both the number and size of metastasis lesions spreading from the breast to the lung in vivo. We show that invasion impairment is due to the inhibition of key effectors of the epithelial-mesenchymal transition. We have developed Lumifluor patient-derived xenograft models and assessed the effect of our inhibitors at various stages during the process of metastases. We have identified CK1δ as an efficacious therapeutic target with dual potential for triggering apoptosis of breast tumor cells and impairing metastatic spread from the primary tumor. Citation Format: Bayle S, Lafitte M, Quereda V, Roush WR, Duckett DR. Targeting of casein kinase 1δ inhibits triple negative breast cancer metastasis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-01-05.